2-229025670-C-T

Variant names:

• chr2-229025670-C-T
• rs544315038
• NM_001100818.2:c.616G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001100818.2(PID1):​c.616G>A​(p.Glu206Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000075 in 1,613,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: PID1 NM_001100818.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79
• Publications: 0 publications found

Genes affected

PID1 (HGNC:26084): (phosphotyrosine interaction domain containing 1) Involved in several processes, including mitochondrion morphogenesis; negative regulation of phosphate metabolic process; and positive regulation of macromolecule metabolic process. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008357257).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PID1	NM_001100818.2	c.616G>A	p.Glu206Lys	missense_variant	Exon 3 of 3	ENST00000392055.8	NP_001094288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PID1	ENST00000392055.8	c.616G>A	p.Glu206Lys	missense_variant	Exon 3 of 3	2	NM_001100818.2	ENSP00000375908.3

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000183 AC: 46 AN: 250696 AF XY: 0.000177

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00223

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000726 AC: 106 AN: 1460996 Hom.: 0 Cov.: 31 AF XY: 0.0000743 AC XY: 54 AN XY: 726610

African (AFR) AF: 0.0000299 AC: 1 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00116 AC: 46 AN: 39654

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1111246

Other (OTH) AF: 0.000133 AC: 8 AN: 60372

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74486

African (AFR) AF: 0.0000240 AC: 1 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000902 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.709G>A (p.E237K) alteration is located in exon 4 (coding exon 3) of the PID1 gene. This alteration results from a G to A substitution at nucleotide position 709, causing the glutamic acid (E) at amino acid position 237 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	.;.;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.098
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0084	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;.;.;N
PhyloP100		3.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.23	N;N;N;N
REVEL	Benign	0.048
Sift	Benign	0.032	D;D;D;T
Sift4G	Uncertain	0.019	D;D;D;D
Polyphen		0.0070	B;B;B;B
Vest4		0.17
MVP		0.32
MPC		0.24
ClinPred		0.11	T
GERP RS		5.0
Varity_R		0.21
gMVP		0.41
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs544315038; hg19: chr2-229890386; COSMIC: COSV62472921; COSMIC: COSV62472921;